Cancer metastasis occurs when individual cancer cells in existing tumors detach from their neighbors, invade local tissues, migrate to distant sites, and establish new tumors at those locations. Epithelial tumors of epithelial origin, which account for 80% of all new cancer diagnoses, are likely to undergo metastasis. Metastasis greatly complicates treatment and increases lethality, particularly since many epithelial primary tumors are not directly life threatening. Significant interest has developed in designing strategies that reduce or prevent metastatic cellular behavior, increasing the effectiveness of existing therapies.
Initiation of metastasis is associated with mutation or expression changes of the MET receptor. MET is activated by its endogenous ligand, scatter factor, or hepatocyte growth factor (HGF). MET is a receptor tyrosine kinase. It has been demonstrated that small molecule inhibitors of MET's kinase activity can prevent the cellular response to MET activation, whether by ligand or by alterations in MET sequence or expression levels. MET inhibitors have been advanced as potential anti-cancer agents. MET signaling is also associated with resistance of cancer cells to radiation treatment. Thus, MET inhibitors can be used to increase cancer susceptibility to radiation therapies that are designed to eliminate tumors.
Signal transduction downstream of MET has not been well defined. The series of events that leads from MET receptor activation to the cellular response remains unclear. Thus, efforts to design inhibitors of MET pathway signaling at points downstream of the MET receptor have been unproductive. Such inhibitors are likely to be more broadly effective than MET inhibitors in treating cancer, as signaling from other receptor systems could converge on the same biological circuits used downstream of MET. Direct MET receptor inhibitors are limited to instances where MET signal transduction is improperly activated at the level of MET itself, while inhibitors that act on MET signaling at points downstream of MET itself will be useful where MET signaling is improperly activated at any level at or above the point of inhibition.